A number of compounds have been employed as carriers for biologically useful molecules in preparing conjugates that are alleged to be tolerogenic. For example, Benacerraf, Katz, and their colleagues investigated and described the use of conjugates of the random co-polymer D-glutamic acid/D-lysine, referred to as D-GL in earlier literature (hereinafter D-EK) with haptens and various antigens to induce specific immune tolerance. See U.S. Pats. Nos. 4,191,668 and 4,220,565.
Other investigators have studied conjugates of nucleosides or DNA with other carriers. Borel et al. (Science (1973) 182:76) evaluated the ability of isogenic mouse IgG-nucleoside conjugates to reduce the antibody response to denatured DNA in young animals of the NZB mouse strain. In separate studies Parker et al. (J. Immunol. (1974) 113:292) evaluated the effect of denatured DNA conjugated to poly-D-lysine and/or cyclophosphamide on the progression of the above-described syndrome in NZB mice.
In a later article (Ann NY Acad Sci (1986) 475:296-306) Borel et al. describe oligonucleotide-immunoglobulin conjugates. Borel et al. (J Clin Invest (1988) 82:1901-1907 or U.S. Pat. No. 4,650,675) have described in vitro studies using conjugates of human immunoglobulin linked to DNA. U.S. Pat. No. 5,126,131 (Dintzis et al.) also relates to conjugates comprising carriers and molecules involved in immune responses.
Other references describe conjugates of nonimmunogenic polymers and immunogens (Sasaki et al., Scand. J. Immun. (1982) 16:191-200; Sehon, Prog. Allergy (1982) 32:161-202; Wilkinson et al., J. Immunol. (1987) 139:326-331, and Borel et al., J. Immunol. Methods (1990) 126:159-168).
In commonly-owned U.S. Ser. No. 07/914,869, U.S. Pat. Nos. 5,162,515, and 07/652,658, conjugates comprising polymeric carriers such as D-EK, polyethylene glycol, poly-D-lysine, polyvinyl alcohol, polyvinyl pyrrolidone and immunoglobulins are described.
In sum, applicants believe that the prior art shows only ill-defined chemical compounds or compounds with numerous non-specific attachment sites employed as valency platform molecules in conjugates. Because the valency of such compounds, the specific location of the attachment sites, and the number of attachment sites are unpredictable and fluctuate widely, prior art conjugates comprising such compounds cannot be made reproducibly and show wide ranges in their reported activity.